The subject invention relates to certain novel analogs of the naturally occurring prostaglandins. Specifically, the subject invention relates to novel Prostaglandin F analogs. The subject invention further relates to methods of using said novel Prostaglandin F analogs. Preferred uses include methods of treating bone disorders and glaucoma.
Naturally occurring prostaglandins (PGA, PGB, PGE, PGF, and PGI) are C-20 unsaturated fatty acids. PGF2a, the naturally occurring Prostaglandin F in humans, is characterized by hydroxyl groups at the C9 and C11 positions on the alicyclic ring, a cis-double bond between C5 and C6, and a trans-double bond between C13 and C14. Thus PGF2a has the following formula: 
Analogs of naturally occurring Prostaglandin F have been disclosed in the art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra and Johnson on May 17, 1977; German Patent No. DT-002,460,990 issued to Beck, Lerch, Seeger, and Teufel published on Jul. 1, 1976; U.S. Pat. No. 4,128,720 issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8, 1977; U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4, 1973; P. W. Collins and S. W. Djuric, xe2x80x9cSynthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogsxe2x80x9d, Chem. Rev. Vol. 93 (1993), pp. 1533-1564; G. L. Bundy and F. H. Lincoln, xe2x80x9cSynthesis of 17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG1 Seriesxe2x80x9d, Prostaglandins, Vol. 9 No. 1 (1975), pp. 1-4; W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens, xe2x80x9cLuteolytic Prostaglandins: Synthesis and Biological Activityxe2x80x9d, Prostaglandins, Vol. 17 No. 2 (1979), pp. 301-311; C. liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, xe2x80x9cDerivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2xcex1 Isopropyl Ester: Potential Antiglaucoma Agentsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
Naturally occurring prostaglandins are known to possess a wide range of pharmacological properties. For example, prostaglandins have been shown to: relax smooth muscle, which results in vasodilatation and bronchodilatation, to inhibit gastric acid secretion, to inhibit platelet aggregation, to reduce intraocular pressure, and to induce labor. Although naturally occurring prostaglandins are characterized by their activity against a particular prostaglandin receptor, they generally are not specific for any one prostaglandin receptor. Therefore, naturally-occurring prostaglandins are known to cause side effects such as inflammation, as well as surface irritation when administered systemically. It is generally believed that the rapid metabolism of the naturally occurring prostaglandins following their release in the body limits the effects of the prostaglandin to a local area. This effectively prevents the prostaglandin from stimulating prostaglandin receptors throughout the body and causing the effects seen with the systemic administration of naturally occurring prostaglandins.
Prostaglandins, especially prostaglandins of the E series (PGE), are known to be potent stimulators of bone resorption. PGF2a has also been shown to be a stimulator of bone resorption but not as potent as PGE2. Also, it has been demonstrated that PGF2a has little effect on bone formation as compared to PGE2. It has been suggested that some of the effects of PGF2a on bone resorption, formation and cell replication may be mediated by an increase in endogenous PGE2 production.
In view of both the wide range of pharmacological properties of naturally occurring prostaglandins and of the side effects seen with the systemic administration of these naturally occurring prostaglandins, attempts have been made to prepare analogs to the naturally occurring prostaglandins that are selective for a specific receptor or receptors. A number of such analogs have been disclosed in the art. Though a variety of prostaglandin analogs have been disclosed, there is a continuing need for potent, selective prostaglandin analogs for the treatment of a variety diseases and conditions.
The invention provides novel PGF analogs. In particular, the present invention relates to compounds having a structure according to the following formula: 
wherein R1, R2, R3, R4, R5, R6, W, X, Z, a, b, and p are defined below.
This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceutically-acceptable salts. biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as bone disorders and glaucoma. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for bone disorders and glaucoma using theses compounds or the compositions containing them.
Terms and Definitions
xe2x80x9cAcylxe2x80x9d is a group suitable for acylating a nitrogen atom to form an amide or carbamate or an oxygen atom to form an ester group. Preferred acyl groups include benzoyl, acetyl, tert-butyl acetyl, para-phenyl benzoyl, and trifluoroacetyl. More preferred acyl groups include acetyl and benzoyl. The most preferred acyl group is acetyl.
xe2x80x9cAlkylxe2x80x9dis a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl have one or two branches, preferably one branch. Preferred alkyl are saturated. Unsaturated alkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond. Alkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkyl are mono-, di-, or trisubstituted. The substituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.
xe2x80x9cAromatic ringxe2x80x9d is an aromatic hydrocarbon ring. Aromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic aromatic rings contain from about 5 to about 10 carbon atoms, preferably from 5 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring. Aromatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred aromatic rings include naphthyl and phenyl. The most preferred aromatic ring is phenyl.
xe2x80x9cBone disorderxe2x80x9d means the need for bone repair or replacement. Conditions in which the need for bone repair or replacement may arise include: osteoporosis (including post menopausal osteoporosis, male and female senile osteoporosis and corticosteroid induced osteoporosis), osteoarthritis, Paget""s disease, osteomalacia, multiple myeloma and other forms of cancer, prolonged bed rest, chronic disuse of a limb, anorexia, microgravity, exogenous and endogenous gonadal insufficiency, bone fracture, non-union, defect, prosthesis implantation and the like.
xe2x80x9cCarbocyclic aliphatic ringxe2x80x9d is a saturated or unsaturated hydrocarbon ring. Carbocyclic aliphatic rings are not aromatic. Carbocyclic aliphatic rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic aliphatic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic aliphatic rings contain from 8 to 12 carbon atoms, preferably from 9 to 10 carbon atoms in the ring. Carbocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred carbocyclic aliphatic rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. More preferred carbocyclic aliphatic rings include cyclohexyl, cycloheptyl, and cyclooctyl.
xe2x80x9cHaloxe2x80x9d is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chloro and fluoro, especially fluoro.
xe2x80x9cHaloalkylxe2x80x9d is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred haloalkyl are C1-C12; more preferred are C1-C6; more preferred still are C1-C3. Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.
xe2x80x9cHeteroalkylxe2x80x9d is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 1 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated heteroalkyl have one or two double bonds or one triple bond. more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or trisubstituted. The substituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.
xe2x80x9cHeteroaromatic ringxe2x80x9d is an aromatic ring containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 member atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heteroaromatic rings contain from 8 to 12 member atoms, preferably 9 or 10 in the ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo, haloalkyl, and phenyl. Preferred heteroaromatic rings include thienyl, thiazolo, purinyl, pyrimidyl, pyridyl. and furanyl. More preferred heteroaromatic rings include thienyl, furanyl, and pyridyl. The most preferred heteroaromatic ring is thienyl.
xe2x80x9cHeteroatomxe2x80x9d is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
xe2x80x9cHeterocyclic aliphatic ringxe2x80x9d is a saturated or unsaturated ring containing carbon and from 1 to about 4 heteroatoms in the ring, wherein no two heteroatoms are adjacent in the ring and no carbon in the ring that has a heteroatom attached to it also has a hydroxyl, amino, or thiol group attached to it. Heterocyclic aliphatic rings are not aromatic. Heterocyclic aliphatic rings are monocyclic, or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic aliphatic rings contain from about 4 to about 10 member atoms (carbon and heteroatoms), preferably from 4 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heterocyclic aliphatic rings contain from 8 to 12 member atoms, preferably 9 or 10 in the ring. Heterocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred heterocyclic aliphatic rings include piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperdyl.
xe2x80x9cLower alkylxe2x80x9d is an alkyl chain comprised of 1 to 6, preferably 1 to 4 carbon atoms.
xe2x80x9cPhenylxe2x80x9d is a monocyclic aromatic ring which may or may not be substituted with from about 1 to about 4 substituents. The substituents may be fused but not bridged and may be substituted at the ortho, meta or para position on the phenyl ring, or any combination thereof. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents on the phenyl ring include halo and haloalkyl. The most preferred substituent is halo. The preferred substitution pattern on the phenyl ring is ortho or meta. The most preferred substitution pattern on the phenyl ring is meta.
The subject invention involves compounds having the following structure: 
In the above structure, R1 is CO2H, C(O)NHOH, CO2R7, CH2OH, SO2R7, C(O)NHR7, C(O)NHS(O)2R7, or tetrazole; wherein R7 is alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring. Preferred R7 is methyl, ethyl, and isopropyl. Preferred R1 is CO2H, C(O)NHOH, CO2R7, C(O)NHSO2R7, and tetrazole. Most preferred R1 is CO2H and CO2R7.
In the above structure, W is O, NH, S, S(O), S(O)2, or (CH2)m; wherein m is an integer from 0 to about 3. Preferred W is O and (CH2)m. Most preferred W is (CH2)1.
In the above structure, R2 is H and R3 is H or lower alkyl, or R2 and R3 together form a covalent bond.
In the above structure, R4 is H, alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring, provided that when each R5 and R6 is H, R4 is other than methyl. Preferred R4 is H and lower alkyl. Most preferred R4 is H.
In the above structure, each R5 is independently selected from the group consisting of H, CH3, and C2H5. Preferred R5 is H and CH3. Most preferred R5 is H.
In the above structure, X is NHR8 or OR8, wherein each R8 is independently selected from the group consisting of H, acyl, alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, and monocyclic heteroaromatic ring. Preferred R8 is H. Preferred X is OR8. Most preferred X is OH.
In the above structure, each R6 is independently selected from the group consisting of H, CH3, C2H5, OR8, and NHR8. Preferred R6 is H, CH3, C2H5, OR8. Most preferred R6 is H and CH3.
In the above structure, Z is H, methyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring, bicyclic carbocyclic aliphatic ring, bicyclic heterocyclic aliphatic ring, bicyclic aromatic ring, or bicyclic heteroaromatic ring. Preferred Z is monocyclic aromatic ring and monocyclic heteroaromatic ring. More preferred Z is thienyl and phenyl.
In the above structure, a and b are independently selected from the group consisting of single bond, cis double bond, and trans double bond. Preferred a is single bond or cis double bond. Preferred b is single bond or trans double bond. When Z is H or methyl, preferred a is cis or trans double bond, preferably cis, and preferred b is cis or trans double bond, preferably trans.
In the above structure, p is an integer from 0 to about 6, preferably 2 or 3, most preferably 2.
The invention also includes optical isomers, diastereomers and enantiomers of the above structure. Preferred stereochemistry at all stereocenters of the compounds of the invention mimic that of naturally occurring PGF2a.
It has been discovered that the novel PGF analogs of the subject invention are useful for treating bone disorders, especially those that require a significant increase in bone mass, bone volume, or bone strength. Surprisingly, the compounds of the subject invention have been found to provide the following advantages over known bone disorder therapies: (1) An increase in trabecular number through formation of new trabeculae; (2) An increase in bone mass and bone volume while maintaining a more normal bone turnover rate; and/or (3) An increase in bone formation at the endosteal surface without increasing cortical porosity.
In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. For example, the bone activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to increase bone volume, mass, or density. An example of such assays is the ovariectomized rat assay.
In the ovariectomized rat assay, six-month old rats are ovariectomized, aged 2 months, and then dosed once a day subcutaneously with a test compound. Upon completion of the study, bone mass and/or density can be measured by dual energy x-ray absorptometry (DXA) or peripheral quantitative computed tomography (pQCT), or micro computed tomography (mCT). Alternatively, static and dynamic histomorphometry can be used to measure the increase in bone volume or formation.
Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein: C. liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, xe2x80x9cDerivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2xcex1 Isopropyl Ester: Potential Antiglaucoma Agentsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
Compounds useful in the subject invention can be made using conventional organic syntheses. A particularly preferred synthesis is the following general reaction scheme: 
In Scheme 1, R1, R2, R3, R4, R5, R6 W, X, Z, and P are as defined above unless defined otherwise. The Corey Aldehyde (S1a) depicted as starting material for Scheme 1 is commercially available (such as from Aldrich Chemical or Cayman Chemical).
In the above Scheme 1, Corey Aldehyde is commercially-available with either a silyl group (P1) or an ester group (P1) attached to the alcohol. The preferred protecting groups include tert-butyldimethylsilyl, acetate, benzoate, and para-phenyl benzoate. The most preferred protecting group is tert-butyldimethylsilyl.
The Corey aldehyde (S1a) is first reacted with an aldehyde protecting group to make a ketal or acetal. Examples of this type of protection are found in Greene and Wuts, Protecting Groups in Organic Synthesis, 2d ed., Wiley and Sons, N.Y. 1991. In this case, especially preferred are cyclic ketals and acetals. The aldehyde (S1a) is reacted with the appropriate 1,2-diol and a suitable acidic catalyst. The solvent can be the diol, and an anhydrous solvent, such as ether or dichloromethane. Particularly useful is 1,2-bis-TMS ethylene glycol to effect this transformation in ether at room temperature.
The ketal-protected S1a may then undergo a routine of protection/deprotection if desired, to exchange the P1 group for a more suitable one, using procedures known in the art. Particularly useful is the exchange of a silyl group for an acyl group, and vice versa. Also useful is the exchange of a silyl or acyl group for an o-bromo-benzyl ether group.
The compound (S1b) is then subjected to a DIBAL reduction to make the hemiacetal. This intermediate is not isolated but reacted as soon as possible with a Wittig salt to form an alkene (S1c). Particularly preferred Wittig salts are derived from omega bromo- four to five carbon straight chain carboxcyclic acids and 3-oxo-carboxcyclic acids. These are conveniently combined with triphenylphosphine in a suitable solvent to form the reactive Wittig salts. Other preferred reagents include straight chain omega-bromo tetrazoles and primary nitrites.
The alkene (S1c) is typically not isolated, but reacted crude with diazomethane in diethyl ether or, preferably, with TMS diazomethane in methanol to give S1d. In addition, a suitable protecting group may be placed on the C9 alcohol and/or the alkene may be reduced at this time. The compound S1d is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, it is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc/hexanes as the eluent.
The cyclic ketal of S1d is removed with acid or acidic ion exchange resin in a suitable solvent to give the free aldehyde. Preferred solvents include THF/water mixtures. The resulting aldehyde (S1e) is not isolated but reacted with ketone-stabilized phosphonium salts. These are generally referred to as xe2x80x9cWadsworth-Horner-Emmonsxe2x80x9d reagents. This reaction requires a mild base. Examples of suitable bases include sodium carbonate or triethyl amine. The product ketone (S1f) is purified by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the ketone (S1f) is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
As seen in Scheme 1 above, the ketone (S1f) can be reacted in three ways. Reduction of the ketone with a reducing agent such as the Luche reagent, effects an alcohol at C-15, as illustrated by S1g.
At this point, the alcohols of S1g at C-9 and C-15 may be protected, if needed or desired. If so, the alcohols can be protected as described previously herein. The S1g compound containing protected or unprotected alcohols is then treated with a deprotecting agent to release selectively P1, on C-11. Examples of such selective deprotection reactions are given in Greene and Wuts.
Alternatively, when P1 is the o-bromobenzyl ether, reduction of the bromine with a radical reducing agent such as (n-Bu)3SnH will cause the radical-induced oxidation of C-11 to the ketone without needing protection. In addition, some PGD analogs are commercially-available with this oxidation at C-11. These compounds can be directly taken on from this step.
Compounds of the type S1g can be converted into compounds of Formula I by the addition of hydroxylamine or alkyoxyamines. After this addition, removal of protecting groups, if any, yields compounds of Formula I. Compounds depicted by Formula I are exemplified in Examples 1-25 and 28-34.
Compounds of Formula I may be converted into compounds of Formula II by reducing the oxime bond with a selective reducing agent. The preferred reducing agent is sodium cyanoborohydride. Compounds depicted by Formula II are exemplified in Examples 35-36 and 38-40.
The ketone (S1f) can also be converted into compounds of the type S1j. This occurs by the addition of suitable nucleophile to the ketone (S1f). Examples of nucleophiles include methyl magnesium bromide. Using substantially the same techniques described above, the compounds of the type S1j can be converted into compounds of Formula III, and compounds of Formula III can be converted into compounds of Formula IV. Compounds depicted by Formula III are exemplified in Examples 26-27 and 41-43, and compounds depicted by Formula IV are exemplified in Examples 37 and 44.
Compounds of the type S1f can also be reacted to give compounds of the type S1m by reacting the ketone at C-15 with an active amine. Examples of reactive amines include methyl amine and ethyl amine. The products can be reduced or can react with nucleophiles using standard techniques, and the reduction can also extend to reduce the alkenes, if desired, using a reagent such as hydrogen gas over palladium on carbon. Alternatively, sodium cyanoborohydride will selectivity reduce the imine without disrupting the alkenes. Finally, a suitable nucleophile, preferably such as a methyl cerium reagent, can add to the imine. Addition of the methylcerium nucleophile (xcx9c1.5 equiv.) is described in T. Imamoto, et al., xe2x80x9cCarbon-Carbon Bond Forming Reactions Using Cerium Metal or Organocerium (III) Reagentsxe2x80x9d, J. Org. Chem. Vol. 49 (1984) p. 3904-12; T. Imamoto, et al., xe2x80x9cReactions of Carbonyl Compounds with Grignard Reagents in the Presence of Cerium Chloridexe2x80x9d, J. Am. Chem. Soc. Vol. 111 (1989) p. 4392-98; and references cited therein, gives the aminomethyl derivative. In that case, R5 in compound S1n would be a methyl group.
Using the reactions disclosed above for compounds of the type S1g, compounds of Formula V can be made from S1n. Compounds depicted by Formula V are exemplified in Example 45. Compounds of the Formula VI can thus be made from compounds of Formula V. Compounds depicted by Formula VI are exemplified in Examples 46.
Compounds of Formula VII can be made from sulfonation or hydroxylamination of compounds of Formula I. Compounds depicted by Formula VII are exemplified in Examples 47-48.
These compounds are isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization.
The following non-limiting examples illustrate the compounds, compositions, and uses of the present invention.